WO2021112174A1 - Procédé thérapeutique antimicrobien optique - Google Patents

Procédé thérapeutique antimicrobien optique Download PDF

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WO2021112174A1
WO2021112174A1 PCT/JP2020/045022 JP2020045022W WO2021112174A1 WO 2021112174 A1 WO2021112174 A1 WO 2021112174A1 JP 2020045022 W JP2020045022 W JP 2020045022W WO 2021112174 A1 WO2021112174 A1 WO 2021112174A1
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target
igy
infrared light
bacterium
specific complex
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PCT/JP2020/045022
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English (en)
Japanese (ja)
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和秀 佐藤
裕智 安井
善之 中川
朋浩 紅
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国立大学法人東海国立大学機構
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Publication of WO2021112174A1 publication Critical patent/WO2021112174A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to photoantibacterial therapy. More specifically, the present invention relates to a target-specific complex that exhibits target-selective damaging activity using near-infrared light irradiation, its use, and the like.
  • NIR-PIT Near-infrared ray immunotherapy
  • IR-PIT is a monoclonal antibody bound to a photosensitizer (eg IRdye700DX (IR700)) that reacts with cancer cells and then is selectively irradiated with near-infrared light. It is a new cancer treatment that destroys the cancer cell membrane. Clinical trials have also been conducted for head and neck cancers targeting EGFR, with good results, and Phase 3 clinical trials are currently underway. Recently, it has been clarified that the mechanism showing the antitumor effect of NIR-PIT is a photochemical reaction completely different from the existing antitumor treatment (see Non-Patent Document 1). It should be noted that Patent Documents 1 to 3 propose that NIR-PIT is used for treatment of tumors and the like.
  • NIR-PIT is a technology with high potential due to its unique mechanism of action, and further application can be expected. Therefore, it is an object of the present invention to provide a new use of NIR-PIT.
  • IgG monoclonal antibody is usually used as an antibody that binds a photosensitizer.
  • IgY immunoglobulin
  • Y Tori egg yolk immunoglobulin
  • IgY is an antibody peculiar to birds.
  • Chicken IgY which can be said to be a representative of IgY, is the main immunoglobulin in spawning chickens and transfers from serum to egg yolk in order to impart passive immunity. Since chicken IgY can be collected from chicken eggs, it can be easily collected in high concentration. In other words, it can be prepared inexpensively and in large quantities.
  • IgY shows no side effects, resistance or toxic residues in contrast to antibiotics. Therefore, IgY is attracting attention as a new means of controlling infectious diseases, which is different from antibiotics. So far, it has been reported that IgY is suppressed against pathogens such as Escherichia coli, Salmonella typhimurium enterocolitica, Salmonella typhimurium enterocolitica, and Galibacterium analyst (see, for example, Non-Patent Document 2). ). However, it cannot be said that the effect is sufficiently high, and there are many practical problems such as the need for continuous administration in order to enhance the effect.
  • the present inventors considered that the combination of NIR-PIT and IgY would be an effective therapeutic means for infectious diseases, etc., and a target in which a near-infrared photosensitizer was linked to a chicken-derived IgY polyclonal antibody.
  • a specific structure was prepared and its effect and practicality were verified.
  • the antibacterial effect of NIR-PIT using IgY polyclonal antibody was exhibited very high and promptly. It can be said that obtaining a rapid effect is a particularly preferable feature as a means of attacking bacteria and fungi whose growth speed is high.
  • the target-specific structure is reactive with related species in addition to the specific Candida albicans, which is the original antigen of IgY used, but not with human cells. It was. These facts mean that they can be effective against a wide range of bacterial species while ensuring high safety, and support their high practicality. In addition, the fact that a bactericidal effect was confirmed against Candida, a fungus having a tough cell wall structure, indicates that the target-specific structure has a strong damaging activity and its application range is wide.
  • a target-specific complex having a structure in which a near-infrared light-sensitive substance is linked to a target-specific IgY classified as a bacterium, fungus or mold, virus, parasite, parasite or rickettsia.
  • Bacteria selected from the group consisting of Pseudomonas, Asinetobacter, Dactophila, Streptococcus, Enterococcus, Escherichia coli, Shigera, Salmonella, Enterobacter and Klebsiella.
  • the target-specific complex according to [2], wherein the fungus or mold is a bacterial species selected from the group consisting of Enterobacter, Aspergillus, Mucor and Cryptococcus fungi.
  • the target-specific complex according to any one of [1] to [3], wherein IgY is a polyclonal antibody.
  • a treatment method including the following steps (1) and (2): (1) A step of administering the composition according to [8] to a therapeutic subject and binding the target-specific complex to the target. (2) A step of irradiating the target with near-infrared light.
  • CA-IgY Candida albicans-IgY
  • IR700 Candida albicans-IgY
  • the binding between CA-IgY and IR700 was confirmed by protein staining (left) and fluorescence staining (right).
  • CA-IgY-IR700 was added to C. albicans seeded in tubes at each concentration, incubated at 37 ° C. for 1 hour, and then the fluorescence intensity was measured by flow cytometry.
  • CA-IgY-IR700 group with applying CA-IgY-IR700 and not irradiating near infrared light
  • Light group near red
  • the tumor area was compared and evaluated between the IgY-PAT group (irradiating near-infrared light after applying CA-IgY-IR700) and the IgY-PAT group (irradiation with external light only).
  • the first aspect of the present invention relates to a "target-specific complex", which is a structure that exhibits specific binding to a target (target of attack) and can exert damaging activity.
  • the target-specific complex of the present invention has a structure in which a near-infrared light-sensitive substance is linked to an antibody against the target.
  • the damaging activity is an action or effect that impairs (damages) the target, and brings about death of the target, suppression of proliferation, detoxification, removal, and the like. If the target is a bacterium or a fungus / mold, the term “damage activity" can be replaced with "antibacterial activity”.
  • IgY is used as the antibody.
  • IgY is an antibody characteristic of birds. For example, IgY of poultry such as chickens and quails can be adopted. IgY is abundantly contained in egg yolk in addition to serum, and is also called egg yolk antibody. Due to the high abundance in egg yolk, it is possible to relatively easily and in large quantities prepare target-specific IgY from the egg yolk of antigen-sensitized birds (typically chickens).
  • Target-specific IgY may be prepared by a conventional method. The following is an example of a method for preparing target-specific IgY.
  • antigens target bacteria, fungi, etc.
  • a part of bacteria, fungi and the like may be used as an antigen.
  • chickens are used as birds.
  • Immunization is repeated as necessary, and eggs are collected when the antibody titer rises sufficiently. It is advisable to check the antibody titer of serum and determine the time of egg collection. Usually, an increase in the IgY concentration in the egg yolk is observed 3 to 7 days after the IgY concentration in the serum reaches the peak. Therefore, it is advisable to collect eggs 10 to 20 days after the final sensitization (immunity) and extract and purify IgY.
  • monoclonal IgY can also be used.
  • Monoclonal IgY can also be prepared by conventional methods (for example, Nishinaka, S. et al. Int Arch Allergy Appl Immunol, 89, 416 (1989); Nishinaka, S. et al. J Immunol Methods, 139, 217 (1991). ); Nishinaka, S. et al. J Vet Med Sci, 58, 1053 (1996)).
  • An example of the preparation method of monoclonal IgY is shown. First, the immune operation is performed in the same procedure as described above.
  • Immunization is repeated as necessary, and when the antibody titer rises sufficiently, antibody-producing cells are removed from the immunized birds.
  • a hybridoma is obtained by a cell fusion method.
  • a clone that produces an antibody having high specificity for the antigen is selected.
  • the antibody of interest is obtained by purifying the culture medium of the selected clone.
  • the desired antibody can also be obtained by growing a desired number of hybridomas, transplanting them into the abdominal cavity of an animal (for example, a mouse), and growing them in ascites to purify the ascites.
  • Affinity chromatography on which an antigen is immobilized is preferably used for purification of the culture solution or ascites. Affinity chromatography in which an antigen is immobilized can also be used. Furthermore, methods such as ion exchange chromatography, gel filtration chromatography, ammonium sulfate fractionation, and centrifugation can also be used. These methods are used alone or in any combination.
  • the targets of attacks by the target-specific complex of the present invention are bacteria, fungi / molds, viruses, parasites, parasites and rickettsia. Infectious to humans or animals under human control (pet / companion animals, industrial animals such as livestock and poultry, laboratory animals, exhibited animals bred and stored in zoos and parks, etc.) Typical targets are those that show and have harmful effects, namely pathogens that can cause infectious diseases (bacteria, fungi / molds, viruses, parasites, parasites, liquettia).
  • the present invention targets the pathogen itself, not the cells infected with the pathogen.
  • IgY which can be prepared in large quantities relatively easily, it is possible to cope with the large number / amount of targets (bacteria, fungi, molds, etc.) and the rapid growth speed of the targets.
  • the target bacteria are not particularly limited, and various bacteria such as gram-negative bacilli, gram-negative cocci, gram-positive cocci, and gram-positive cocci can be targeted.
  • Specific examples of potential target bacteria include Escherichia coli, Shigella (S. dysenteriae, S. frexneri, S. sunnei, etc.), Salmonella (S. typh, S. paratyphi). -A, S. schottmuelleri, S. typhimurium, S. enteritidis, etc.), Enterobacter bacteria (E. aerogenes, E. cloacae, etc.), Klebsiella (K. pneumoniae, K.
  • viridans S. pneumoniae, S. mutans, S. sobrinus, etc.
  • Enterococcus E. faecalis, E. faecium
  • Bacillus B. subtilis, B. anthracis, B. cereus, etc.
  • Listeria L. monocytogenes, etc.
  • Clostridium C. difficile, C. botulinum, C. perfringens, C. tetani, etc.
  • Corynebacterium C. diphtheriae, etc.
  • Branhamella B. catarrhalis, etc.
  • Mycobacteria B. catarrhalis, etc.
  • Mycobacterium M.
  • tuberculosis tuberculosis, M. bovis, M. leprae, M. avium, M. intracellulare, M. kansasii, M. ulcerans, etc.
  • Peptcoccus P. anaerovius, etc.
  • Peptostreptococcus Bacteria Peptostreptococcus
  • Eubacterium E. lentum, etc.
  • Propionibacterium Propi, etc. onibacterium (P.acnes), Lactobacillus (L.plantarum, etc.)
  • Bacteroides B.fragilis, B.melaninogenicus, etc.
  • Fusobacterium F.gonidiaformans, etc.
  • Bacteria of the genus Porphyromonas P. gingivalis, etc.
  • Bacteria of the genus Prevotella Prevotella, intermediate, etc.
  • Aggregatibacter A. actinomycetemcomitans, etc.
  • Treponema genus Bacteria can be mentioned.
  • fungi and fungi examples are Candida (C. albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, etc.), Aspergillus (A). Fumigatus, A. flavus, A. niger, etc.), Cryptococcus (C. neoformans, etc.), Mucor (M. circinelloides, etc.), Rhizopus (R. oryzae, etc.) R. microsporus, etc.), Cunninghamella (C. bertholletiae, etc.), Apophysomyces (A. elegans), Sakseneae (S.
  • viruses that can be targeted include natural pox virus, vactinia virus, infectious irritation virus, herpesvirus 1 (HSV-1), herpesvirus 2 (HSV-2), and varicella / herpesvirus 6 (HSV-2).
  • HHV-3 Cytomegalovirus
  • HHV-5 Human Herpesvirus 6
  • HHV-7 Human Herpesvirus 7
  • HHV-4 Epstein Bar Virus
  • HHV-4 Human Herpesvirus 8
  • HHV-8 also known as Kaposi sarcoma-related herpesvirus (KSHV)
  • KSHV Kaposi sarcoma-related herpesvirus
  • adenovirus human papillomavirus, parvovirus B19, dicavirus
  • hepatitis B virus influenza virus, measles virus, mumpsvirus, RS virus, human immunodeficiency virus (HIV), human T lymphophilic virus (HTLV-1), coronavirus, lassavirus, eczema virus, Japanese encephalitis virus, yellow fever virus, dengue fever virus, hepatitis C virus, huntervirus, poliovirus, coxsackie virus, echo Viruses, rhinoviruses, hepatitis A virus,
  • examples of parasites that can be targeted include malaria (P. falciparum, P. vivox, P. malariae, etc.), Leishimania (L. donovani, L braziliensis, etc.), and Cryptosporidium. (C.parvum, etc.), Trypanosoma (T.brucei, T, cruzi, etc.), Trichomonas (T.vaginalis, etc.), Toxoplasma (T.gondii, etc.), Babesia (B) Microti, etc.), Entamoeba (E.hitsolytica, etc.), Gicardia (G. intestinalis, G.muris, etc.), Cryptosporidium (C.parvum, etc.).
  • malaria P. falciparum, P. vivox, P. malariae, etc.
  • Leishimania L. donovani, L braziliensis, etc.
  • Cryptosporidium C.parvum, etc.
  • Trypanosoma T.
  • examples of parasites that can cause infectious diseases are roundworms (Ascaris) (Ascaris lumbricoides, etc.), Zubini worms (Ancylostomoa duodenale), Necator americanus, worms (Enterobius vermicularis), and threadworms (Strongyloides stercoralis).
  • Anisakis A. simplex, A. physeteris, etc.
  • Pseudoterranova P. decipiens
  • Wunchereri bancroft Brugia malayi
  • Gnathostoma G. nipponicum, G. spinigerum, etc.
  • Trichinella T. spiralis, T.
  • examples of rickettsia that can cause infectious diseases include rickettsia (R. rickettsia, R. prowazekii, R. typhi, etc.), Orientia (O. tsutsugamushi, etc.), and Ehrlichia. (E. chaffeensis, etc.), Anaplasma (A. phafocytophilum, etc.), Coxiella (C. burnetii, etc.) can be mentioned.
  • polyclonal IgY may be adopted.
  • polyclonal IgY it does not bind to the human body and can exhibit pathogen-selective yet damaging activity against a relatively wide range of targets.
  • monoclonal IgY is suitable when constructing a target-specific structure targeted to a specific pathogen (for example, a specific strain or strain), in other words, when it is necessary to enhance selectivity or specificity ( However, even in this case, polyclonal IgY may be used).
  • the present invention utilizes the principle of photoimmunotherapy (PIT). Therefore, a near-infrared light-sensitive substance is linked to the target-specific IgY.
  • a phthalocyanine dye is used as a near-infrared light sensitive substance.
  • Phthalocyanine pigments are a group of photosensitizer compounds having a phthalocyanine ring system. For example, WO 2005/099689 and US Pat. No. 7,005,518 can be referred to for the synthesis method and usage (use) of various phthalocyanine pigments.
  • a phthalocyanine pigment having an absorption peak in the near infrared (NIR) region and strongly absorbing near infrared rays to emit fluorescence is used. More specifically, a phthalocyanine dye having an absorption peak at 600 nm to 950 nm, more preferably 660 nm to 740 nm, and even more preferably 680 nm to 720 nm is used.
  • IR700 (IRDye® 700DX) can be mentioned as a particularly preferable phthalocyanine pigment.
  • IR700 is commercially available from LI-COR (LI-COR Biosciences).
  • Amino-reactive IR700 is a relatively hydrophilic dye that can be covalently bound to IgY using, for example, the NHS ester of IR700.
  • the near-infrared light-sensitive substance is directly or indirectly linked to the target-specific IgY via a covalent bond or a non-covalent bond.
  • Non-covalent bonds are achieved, for example, by electrostatic interactions, van der Waals forces, hydrophobic interactions, ⁇ effects, ionic interactions, hydrogen bonds or halogen bonds.
  • a linker is usually used for indirect concatenation.
  • compositions and its use can be formulated to prepare a pharmaceutical composition.
  • a pharmaceutically acceptable carrier carrier, vehicle
  • carriers include water, saline, balanced salt solution, aqueous dextrose, glycerol, mannitol, lactose, starch and magnesium stearate.
  • carriers include water, saline, balanced salt solution, aqueous dextrose, glycerol, mannitol, lactose, starch and magnesium stearate.
  • Remington's Pharmaceutical Sciences by E.W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition (1995) can be referred to.
  • compositions include diluents (lactorose, sucrose, dicalcium phosphate, or carboxymethyl cellulose, etc.), excipients (starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, etc.) Sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc.), lubricants (magnesium stearate, calcium stearate, talc, etc.), pH regulators (acetate, citrate, etc.) Sodium acid, cyclodextrin derivative, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.), emulsifier, solubilizer, isotonic agent, preservative, preservative, etc. may be contained.
  • diluents lactorose, sucrose, dicalcium phosphate
  • the dosage form / shape when formulating is not particularly limited.
  • dosage forms are aerosols, liquids, suspensions, injections, syrups, emulsions, jellies, tablets, pills, powders, fine granules, granules, capsules, external preparations (ointments, patches). , Paps, lotions, pills, suppositories), inhalants, nasal drops and eye drops.
  • the pharmaceutical composition of the present invention contains an amount (that is, a therapeutically effective amount) of the active ingredient necessary for obtaining the expected therapeutic effect (or preventive effect).
  • the amount of the active ingredient in the pharmaceutical composition of the present invention generally varies depending on the dosage form, but the amount of the active ingredient is set in the range of, for example, about 0.001% by weight to about 99% by weight so that a desired dose can be achieved.
  • a further aspect of the present invention relates to the use of the pharmaceutical composition.
  • the pharmaceutical compositions of the present invention are used for the treatment, prevention or amelioration of diseases and conditions.
  • Treatment includes alleviating (mitigating) the symptomatology or concomitant symptom characteristic of the target disease, preventing or delaying the worsening of the symptomatology, and the like.
  • Prevention means preventing or delaying the onset / delay of a disease (disorder) or its symptoms, or reducing the risk of onset / onset.
  • improvement means that the disease (disorder) or its symptoms are alleviated (mild), improved, ameliorated, or cured (including partial cure).
  • treatment, prevention, and improvement are some overlapping concepts, which are difficult to distinguish and capture, and the benefits of doing so are small.
  • treatment for the purpose of prevention or improvement is also included in the concept of the term "therapeutic method”.
  • the pharmaceutical composition of the present invention is typically applied to the treatment, prevention or amelioration of infectious diseases caused by targets (bacteria, fungi / molds, viruses, parasites, parasites, rickettsia).
  • targets bacteria, fungi / molds, viruses, parasites, parasites, rickettsia
  • the pharmaceutical composition of the present invention is utilized for IgY-PAT therapy.
  • infectious diseases include infectious pyoderma (impetigo vesicular, impetigo crust), tan poison, bee folliculitis, folliculitis, furuncle, yo (furuncle).
  • the following steps (1) and (2) are performed.
  • (1) A step of administering the pharmaceutical composition of the present invention to a therapeutic subject and binding the target-specific complex of the present invention to the target (2)
  • the pharmaceutical composition of the present invention is administered to the therapeutic subject.
  • the route of administration may be selected according to the dosage form of the pharmaceutical composition, the treatment policy, and the like. Both oral and parenteral administration (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, or intraperitoneal injection, transdermal, nasal, transmucosal, application to affected areas, application, spray, etc.) can be adopted. Is.
  • these administration routes are not mutually exclusive, and two or more arbitrarily selected administration routes can be used in combination (for example, intravenous injection or the like is performed at the same time as oral administration or after a lapse of a predetermined time). Both systemic administration and topical administration (for example, application, application, spray, etc.
  • animals under the control of humans can be adopted.
  • animals under the control of humans can also be treated.
  • animals under the control of humans can also be treated.
  • animals under the control of humans can also be treated.
  • animals under the control of humans can also be treated.
  • animals under the control of humans can also be treated.
  • the dose of the pharmaceutical composition is set so as to obtain the expected therapeutic effect.
  • Symptoms, patient age, gender, weight, etc. are generally considered in the setting of therapeutically effective doses.
  • Those skilled in the art can set an appropriate dose in consideration of these matters.
  • systemic administration for example, 0.1 to 1000 mg, 0.2 to 500 mg, 0.5 to 100 mg or 1 per 60 kg of body weight.
  • topical administration it is, for example, 0.01 to 50 mg, 0.03 to 30 mg, or 0.05 to 10 mg per 1 cm 2 of the application site.
  • the medical condition of the patient and the duration of effect of the active ingredient can be taken into consideration.
  • the target-specific complex which is the active ingredient thereof, is bound to the target, and then the target is irradiated with near-infrared light (step (2)).
  • irradiation with near-infrared light damages the surface structure of the target (for example, the cell wall in the case of bacteria), and exerts its effects (such as killing the target and suppressing its growth). ..
  • This mechanism of action is different from the mechanism of action of photodynamic therapy (PDT) (which exerts its effect by causing oxidative stress in mitochondria), and brings about a rapid effect.
  • PDT photodynamic therapy
  • the devices include, but are not limited to, a light guide catheter, an endoscopic light guide fiber, a puncture irradiation fiber, a blood vessel light guide catheter, a drain indwelling light guide device, an implantable type, and a sticking type. , A bracelet type device, etc. can be considered.
  • the irradiation conditions of near-infrared light are not particularly limited as long as the damaging activity based on the principle of NIR-PIT can be obtained, but the wavelength of near-infrared light used is, for example, 650 to 740 nm, preferably 670 to 720 nm, and further. It is preferably 680 to 710 nm.
  • the irradiation doses are, for example, at least 1 J cm -2 , at least 2 J cm -2 , at least 5 J cm -2 , at least 10 J cm -2 , at least 20 J cm -2 , at least 30 J cm -2 , at least 40 J cm -2.
  • the irradiation dose is, for example, 5 seconds to 1 hour, 5 seconds to 30 minutes, or 5 seconds to 15 minutes.
  • the irradiation time is preferably 10 seconds or longer, more preferably 1 minute or longer, and even more preferably 3 minutes or longer.
  • the pharmaceutical composition when the pharmaceutical composition is systemically administered by intravenous injection or the like, after administration of the pharmaceutical composition, for example, for 5 minutes to 48 hours, preferably 10 minutes to 24 hours. Irradiation with near-infrared light is carried out over time, more preferably between 15 minutes and 12 hours. In the case of topical administration, it is preferable to set the interval between administration of the pharmaceutical composition and irradiation of near-infrared light shorter than in the case of systemic administration (for example, 1 minute to 12 hours after administration of the pharmaceutical composition). Irradiate near-infrared light during).
  • the interval is not particularly limited. For example, multiple irradiations on the same day at predetermined intervals (for example, 5 minutes to 10 hours), daily irradiation, every other day or every few days, one week or every few weeks, one month or number.
  • Various irradiation schedules can be set, such as irradiation every month.
  • the administration schedule of the pharmaceutical composition in the case of multiple irradiations is not particularly limited. For example, if the interval between the first and second irradiations is short, the pharmaceutical composition is typically administered only prior to the first irradiation. To give another example, if the elapsed time from the previous irradiation is long (for example, one day to several months have passed), it is advisable to administer the pharmaceutical composition again and then perform irradiation. ..
  • antibacterial agents for example, penicillin antibacterial agents, cephem antibacterial agents, carbapenem antibacterial agents, penem antibacterial agents, tetracycline antibacterial agents, ⁇ Treatment with lactamase inhibitors, phosphomycin, vancomycin, aminoglycoside antibacterial agents, macrolide antibacterial agents
  • antibacterial agents for example, penicillin antibacterial agents, cephem antibacterial agents, carbapenem antibacterial agents, penem antibacterial agents, tetracycline antibacterial agents, ⁇ Treatment with lactamase inhibitors, phosphomycin, vancomycin, aminoglycoside antibacterial agents, macrolide antibacterial agents
  • a complex action / effect can be obtained and the therapeutic effect can be increased.
  • the target-specific complex of the present invention is contaminated with pathogens (bacteria, fungi / molds, viruses, parasites, parasites, rickettsia) that can cause infectious diseases (contaminants). ) Can also be used for disinfection or decontamination. That is, a composition for disinfection / decontamination (hereinafter, referred to as "disinfectant of the present invention" for convenience of explanation) can be prepared using the target-specific complex of the present invention.
  • the disinfectant of the present invention is, for example, various facilities / instruments / equipment in medical institutions (hospitals, clinics, nursing homes for the elderly, home-visit nursing care stations, midwifery centers, pharmacies, etc.), osteopathic clinics, osteopathic clinics, acupuncture and moxibustion clinics, etc. (Inspection or surgical equipment, instruments or devices, urinary organs, floors, walls, curtains, furniture, doors, windows, bedding, clothing, etc.) and spaces (in hospital rooms, operating rooms, clean rooms, clean benches, etc.) Disinfection or decontamination, various equipment, utensils, equipment, etc.
  • the disinfectant of the present invention is composed of, for example, a liquid (for example, a spray agent, a lotion), a gel form, or a solid form (for example, a powder), and is used by coating, spraying (spraying), spraying, dropping, or the like.
  • a liquid for example, a spray agent, a lotion
  • a gel form for example, a powder
  • a solid form for example, a powder
  • the disinfectant of the present invention is irradiated with near-infrared light to exert a damaging activity.
  • the irradiation conditions of near-infrared light are the same as in the case of treatment using a pharmaceutical composition.
  • CA-IgY-IR700 Preparation of Candida albicans-IgY (CA-IgY) -IR700 and confirmation of quality 1-1.
  • CA-IgY-IR700 was synthesized.
  • CA-IgY (1.0 mg, 5.4 nmol) and IR700 (47.8 ⁇ g, 24.5 nmol) were incubated with Na 2 HPO 4 (pH 8.5) 0.1 M for 1 hour at room temperature, followed by a Sephadex G50 column (PD-10; The mixture was collected through GE healthcare) (CA-IgY-IR700 solution).
  • the absorbance (wavelength 595 nm) was measured to determine the concentration (protein concentration) of CA-IgY-IR700.
  • concentration of IR700 was determined by measuring the absorbance (wavelength 698 nm), and the number of fluorescent molecules bound to the antibody was confirmed.
  • the above mixed solution was subjected to SDS-PAGE, and the binding between the antibody and IR700 was confirmed. Diluted CA-IgY was used for SDS-PAGE control, and imaging was performed with a Pearl imager (LICOR).
  • albicans species FC18, IFO579, IFO1060, and IFO1385), and related species such as Candida tropicalis (IFO1402), Candida guilliermondii (IFO838), Candida krusei (IFO1162), and A431 (human skin cancer cells).
  • Candida tropicalis IFO1402
  • Candida guilliermondii IFO838
  • Candida krusei IFO1162
  • A431 human skin cancer cells
  • C. albicans JCM1542 was cultured in a liquid medium for 24 hours, then seeded in a tube with 100 ⁇ L of medium in 1 ⁇ 10 5 each, and CA-IgY-IR700 was added. After incubation at room temperature for 4 hours (10 ⁇ g / mL, 50 ⁇ g / mL, 100 ⁇ g / mL, or 200 ⁇ g / mL), near-infrared light (256 J / cm 2 ) was irradiated using an LED with an emission wavelength of 690 nm.
  • CA-IgY-IR700 was adjusted to 200 ⁇ g / mL, and after incubation at room temperature for 4 hours, near-infrared light (32J, 64J,) using an LED with an emission wavelength of 690 nm was used. It was irradiated with 128J and 256J / cm 2). Those subjected to near-infrared light irradiation (256 J / cm 2 ) without adding CA-IgY-IR700 were also evaluated. After the treatment, the number of colonies was measured by the same method to evaluate the viable cell count (Fig. 4).
  • CA-IgY-IR700 200 ⁇ g / mL was reacted in the same manner, and 1 hour after irradiation with near infrared light 256 J / cm 2 1 hour, dead cell staining (Propiodium Iodide: PI staining) was used. It was observed with a confocal microscope and a scanning electron microscope.
  • the next day (Day 1) the emergency bond was removed, and it was evaluated by Pearl imager (LICOR) whether CA-IgY-IR700 could be confirmed in the ulcer area. Then, near infrared light (256 J / cm 2 ) was irradiated with a laser. The transition of the ulcer area was quantitatively evaluated with the ulcer area on the irradiation day as 100%. The ulcer area was photographed and calculated using Image J (open source).
  • the treatment group is the IgY-PAT group, which is a sterile group without C. albicans, a CA group with only C. albicans, and a CA-IgY-IR700 group with CA-IgY-IR700 applied and not irradiated with near-infrared light.
  • the target-specific complex of the present invention (a structure in which a near-infrared light-sensitive substance is linked to IgY) exhibits target-specific damaging activity according to the principle of NIR-PIT and exerts a therapeutic effect.
  • the present invention using IgY which is inexpensive and easy to prepare in large quantities, provides a new therapeutic means capable of coping with the explosive increase in targets in infectious diseases such as bacteria, fungi, and molds, and is effective against various infectious diseases. It is expected to be applied or applied.
  • the present invention is an innovative technique that is different from the conventional antibacterial therapy using IgY alone, and a high therapeutic effect can be obtained. In addition, due to its unique mechanism of action, rapid onset of effects can be expected.
  • the fact that the bactericidal effect on Candida having a tough cell wall structure has been confirmed means that the present invention can be an effective means of attack not only against various Gram-positive bacteria but also against various Gram-negative bacteria and various fungi. To support.
  • target-directing substances include commonly considered binding substances such as antibodies (IgG, IgM, antibody fragments, Minibody, Diabody, etc.), peptides, aptamers, etc., which can be used in place of IgY. ..
  • binding substances such as antibodies (IgG, IgM, antibody fragments, Minibody, Diabody, etc.), peptides, aptamers, etc., which can be used in place of IgY. ..
  • the contents of the articles, published patent gazettes, patent gazettes, etc. specified in this specification shall be cited by reference in their entirety.

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Abstract

La présente invention concerne une nouvelle application de la thérapie d'immunologie par rayon dans le proche infrarouge. En particulier, la présente invention concerne : un complexe spécifique à la cible ayant une structure dans laquelle une substance sensible à la lumière proche infrarouge est liée à l'IgY spécifique aux cibles classées comme bactéries, champignons, moisissures, virus, organismes parasites, insectes parasites, ou Rickettsia ; un procédé thérapeutique utilisant le complexe spécifique à la cible ; et similaires.
PCT/JP2020/045022 2019-12-03 2020-12-03 Procédé thérapeutique antimicrobien optique WO2021112174A1 (fr)

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